1-25563141-T-C

Position:

chr1-25563141-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM5BP4_StrongBP6_Very_StrongBA1

The NM_015627.3(LDLRAP1):c.604T>C(p.Ser202Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.518 in 1,611,136 control chromosomes in the GnomAD database, including 218,659 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S202H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.48 ( 17958 hom., cov: 31)

Exomes 𝑓: 0.52 ( 200701 hom. )

Consequence

LDLRAP1
NM_015627.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.666

Variant links:

Genes affected

LDLRAP1 (HGNC:18640): (low density lipoprotein receptor adaptor protein 1) The protein encoded by this gene is a cytosolic protein which contains a phosphotyrosine binding (PTD) domain. The PTD domain has been found to interact with the cytoplasmic tail of the LDL receptor. Mutations in this gene lead to LDL receptor malfunction and cause the disorder autosomal recessive hypercholesterolaemia. [provided by RefSeq, Jul 2008]

LDLRAP1 links:

LDLRAP1 (HGNC:):

LDLRAP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-25563141-T-CC is described in ClinVar as [Pathogenic]. Clinvar id is 1751270.Status of the report is criteria_provided_single_submitter, 1 stars.

BP4

Computational evidence support a benign effect (MetaRNN=2.5136673E-5).

BP6

Variant 1-25563141-T-C is Benign according to our data. Variant chr1-25563141-T-C is described in ClinVar as [Benign]. Clinvar id is 296982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-25563141-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.533 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LDLRAP1	NM_015627.3 linkuse as main transcript	c.604T>C	p.Ser202Pro	missense_variant	6/9	ENST00000374338.5	NP_056442.2	Q5SW96B3KR97

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
LDLRAP1	ENST00000374338.5 linkuse as main transcript	c.604T>C	p.Ser202Pro	missense_variant	6/9	1	NM_015627.3	ENSP00000363458.4	Q5SW96
LDLRAP1	ENST00000484476.5 linkuse as main transcript	n.326T>C		non_coding_transcript_exon_variant	1/4	1
LDLRAP1	ENST00000488127.1 linkuse as main transcript	n.1074T>C		non_coding_transcript_exon_variant	5/7	2

Frequencies

GnomAD3 genomes

AF:

0.479

AC:

72733

AN:

151808

Hom.:

17949

Cov.:

show subpopulations

Gnomad AFR

AF:

0.354

Gnomad AMI

AF:

0.490

Gnomad AMR

AF:

0.520

Gnomad ASJ

AF:

0.586

Gnomad EAS

AF:

0.475

Gnomad SAS

AF:

0.445

Gnomad FIN

AF:

0.500

Gnomad MID

AF:

0.557

Gnomad NFE

AF:

0.538

Gnomad OTH

AF:

0.525

GnomAD3 exomes

AF:

0.505

AC:

126613

AN:

250530

Hom.:

32729

AF XY:

0.506

AC XY:

68556

AN XY:

135546

show subpopulations

Gnomad AFR exome

AF:

0.351

Gnomad AMR exome

AF:

0.552

Gnomad ASJ exome

AF:

0.581

Gnomad EAS exome

AF:

0.448

Gnomad SAS exome

AF:

0.431

Gnomad FIN exome

AF:

0.504

Gnomad NFE exome

AF:

0.534

Gnomad OTH exome

AF:

0.537

GnomAD4 exome

AF:

0.522

AC:

762025

AN:

1459208

Hom.:

200701

Cov.:

AF XY:

0.521

AC XY:

378270

AN XY:

726082

show subpopulations

Gnomad4 AFR exome

AF:

0.355

Gnomad4 AMR exome

AF:

0.547

Gnomad4 ASJ exome

AF:

0.587

Gnomad4 EAS exome

AF:

0.500

Gnomad4 SAS exome

AF:

0.435

Gnomad4 FIN exome

AF:

0.496

Gnomad4 NFE exome

AF:

0.534

Gnomad4 OTH exome

AF:

0.512

GnomAD4 genome

AF:

0.479

AC:

72780

AN:

151928

Hom.:

17958

Cov.:

AF XY:

0.476

AC XY:

35369

AN XY:

74248

show subpopulations

Gnomad4 AFR

AF:

0.354

Gnomad4 AMR

AF:

0.521

Gnomad4 ASJ

AF:

0.586

Gnomad4 EAS

AF:

0.475

Gnomad4 SAS

AF:

0.446

Gnomad4 FIN

AF:

0.500

Gnomad4 NFE

AF:

0.538

Gnomad4 OTH

AF:

0.523

Alfa

AF:

0.521

Hom.:

42587

Bravo

AF:

0.477

TwinsUK

AF:

0.546

AC:

2025

ALSPAC

AF:

0.539

AC:

2078

ESP6500AA

AF:

0.345

AC:

1519

ESP6500EA

AF:

0.533

AC:

4583

ExAC

AF:

0.499

AC:

60644

Asia WGS

AF:

0.427

AC:

1485

AN:

3478

EpiCase

AF:

0.546

EpiControl

AF:

0.537

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypercholesterolemia, familial, 4

Benign:5

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GENinCode PLC	Jun 30, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 08, 2021	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 13, 2019	Variant summary: LDLRAP1 c.604T>C (p.Ser202Pro) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.51 in 250530 control chromosomes, therefore suggesting the variant is the major allele. Two ClinVar submissions (evaluation after 2014) cite the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 28, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Cardiovascular phenotype

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 02, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Familial hypercholesterolemia

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.69

CADD

Benign

4.9

DANN

Benign

0.60

DEOGEN2

Benign

0.27

Eigen

Benign

-1.9

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.021

LIST_S2

Benign

0.22

MetaRNN

Benign

0.000025

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.8

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.76

REVEL

Benign

0.041

Sift

Benign

0.14

Sift4G

Benign

0.16

Polyphen

0.079

Vest4

0.069

MPC

0.25

ClinPred

0.0090

GERP RS

-2.4

Varity_R

0.073

gMVP

0.24

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over